Our previous studies have demonstrated that the effects of the immune cytokine interferon-? (IFN-?) in immune-mediated demyelinating diseases are mediated, at least in part, by the unfolded protein response (UPR) in oligodendrocytes. Data indicate that some biological effects of IFN-? are elicited through activation of the transcription factor nuclear factor-?B (NF-?B). Interestingly, it has been shown that activation of the pancreatic endoplasmic reticulum kinase (PERK) branch of the UPR triggers NF-?B activation. In this study, we showed that IFN-?-induced NF-?B activation was associated with activation of PERK signaling in the oligodendroglial cell line Oli-neu. We further demonstrated that blockage of PERK signaling diminished IFN-?-induced NF-?B activation in Oli-neu cells. Importantly, we showed that NF-?B activation in oligodendrocytes correlated with activation of PERK signaling in transgenic mice that ectopically express IFN-? in the central nervous system (CNS), and that enhancing IFN-?-induced activation of PERK signaling further increased NF-?B activation in oligodendrocytes. Additionally, we showed that suppression of the NF-?B pathway rendered Oli-neu cells susceptible to the cytotoxicity of IFN-?, reactive oxygen species, and reactive nitrogen species. Our results indicate that the UPR is involved in IFN-?-induced NF-?B activation in oligodendrocytes and suggest that NF-?B activation by IFN-? represents one mechanism by which IFN-? exerts its effects on oligodendrocytes in immune-mediated demyelinating diseases.More...